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Madeleine Petersson-Sjögren,1,2 Jonas Jakobsson,3 H Laura Aaltonen,4,5 Hanna Nicklasson,6,7 Jenny Rissler,1,2,8 Gunnar Engström,9 Per Wollmer,6 Jakob Löndahl1,2 1Division of Ergonomics and Aerosol Technology, Department of Design Sciences, Lund University, Lund, Sweden; 2NanoLund, Lund University, Lund, Sweden; 3Division of Nuclear Physics, Department of Physics, Lund University, Lund, Sweden; 4Department of Translational Medicine, Medical Imaging and Physiology, Lund University, Malmö, Sweden; 5Department of Radiology, University of Washington, Seattle, WA, USA; 6Department of Translational Medicine, Clinical Physiology and Nuclear Medicine, Skåne University Hospital, Malmö, Sweden; 7MVIC Medicon Valley Inhalation Consortium AB, Lund, Sweden; 8Division of Bioeconomy and Health, RISE Research Institutes of Sweden, Borås, Sweden; 9Department of Clinical Sciences, Lund University, Malmö, SwedenCorrespondence: Jakob Löndahl, Division of Ergonomics and Aerosol Technology, Lund University, Box 118, Lund, SE-221 00, Sweden, Email jakob.londahl@design.lth.seBackground: Airspace Dimensions Assessment with nanoparticles (AiDA) is a new method for non-invasive measurement of pulmonary distal airspaces. The aim of this study was to compare AiDA measurements with other pulmonary function variables to better understand the potential of AiDA in a clinical context.Methods: AiDA measurements and pulmonary function tests were performed in 695 subjects as part of the Swedish CArdioPulmonary bioImage Study. The measurement protocol included spirometry, measurement of diffusing capacity of carbon monoxide, oscillometry and pulmonary computed tomography. AiDA indices were compared to all other pulmonary examination measurements using multivariate statistical analysis.Results: Our results show that AiDA measurements were significantly correlated with other pulmonary function examination indices, although covariance was low. We found that AiDA variables explained variance in the data that other lung function variables only influenced to a minor extent.Conclusion: We conclude that the AiDA method provides information about the lung that is inaccessible with more conventional lung function techniques.Keywords: aerosol nanoparticles, respiratory diagnostics with nanoparticles, distal airspaces, COPD diagnostics, airspace dimension assessment with nanoparticles

Georg Rüdiger Schramm,1 Behrouz Mostafavi,1 Eeva Piitulainen,1 Per Wollmer,2 Hanan A Tanash1 1Department of Respiratory Medicine and Allergology, Skåne University Hospital, Lund University, Malmö, Sweden; 2Department of Medical Imaging and Physiology, Skåne University Hospital, Lund University, Malmö, SwedenCorrespondence: Georg Rüdiger SchrammDepartment of Respiratory Medicine and Allergology, Skåne University Hospital, Jan Waldenströms Gata 24, Malmö, S – 205 02, SwedenTel +46 40 33 25 85Fax +46 40 33 74 90Email Georg.Schramm@med.lu.seBackground: Severe hereditary alpha-1-antitrypsin deficiency (AATD) is a known risk factor for the early development of pulmonary emphysema and COPD, especially in smokers. By the Swedish national screening programme carried out from 1972 to 1974, a cohort of individuals with severe (PiZZ) AATD was identified and has been followed up regularly. The aim of this study was to investigate health status, quality of life and lung function in this cohort at the age of 42 years compared with an age-matched control group randomly selected from the population registry.Methods: All study participants answered a questionnaire on smoking habits, symptoms, occupation, exposure to airway irritants and quality of life using Saint George’s Respiratory Questionnaire (SGRQ). They underwent complete pulmonary function tests (PFT) and forced oscillation technique (FOT) for the measurement of airway resistance and reactance. Blood samples were taken for allergies and IgG-subclasses as an indicator of increased risk of airway infections.Results: The residual volume (RV), total lung capacity (TLC) and RV/TLC ratio were significantly higher in the PiZZ ever-smokers compared to the PiMM ever-smokers and PiZZ never-smokers (p < 0.05). The resistance in the upper, small and total airways was significantly lower in PiZZ subjects compared to PiMM subjects (p < 0.05). A greater proportion of PiZZ never-smokers had an FEV1/VC ratio < 0.7 than PiMM never-smokers (p = 0.043). PiZZ subjects with occupational exposure to airway irritants showed a significantly lower FEV1, VC and higher RV/TLC ratio than PiMM individuals with exposure (p < 0.05).Conclusion: At the age of 42, ever-smoking PiZZ individuals have signs of COPD, and also PiZZ never-smokers have early, physiological signs of emphysema.Keywords: alpha-1-antitrypsin deficiency, COPD, lung function, quality of life

Behrouz Mostafavi,1 Sandra Diaz,2 Eeva Piitulainen,1 Berend C Stoel,3 Per Wollmer,4 Hanan A Tanash1 1Department of Respiratory Medicine and Allergology Malmö, Skåne University Hospital, Lund University, Malmö, Sweden; 2Department of Clinical Physiology Malmö, Skåne University Hospital, Lund University, Malmö, Sweden; 3Division of Image Processing, Department of Radiology, Leiden University Medical, Leiden, the Netherlands; 4Department of Translational Medicine, Lund University, Malmö, Sweden Background: Alpha-1-antitrypsin (AAT) deficiency is a hereditary disorder that predisposes to emphysema. A cohort of severe (PiZZ) and moderate (PiSZ) AAT-deficient newborn infants was identified by the Swedish national neonatal AAT screening program in 1972–1974 and has been followed-up since birth. Our aim was to study whether the cohort has signs of emphysema in pulmonary function tests (PFTs) and computed tomography (CT) densitometry at 38 years of age in comparison with an age-matched control group, randomly selected from the population registry. Methods: Forty-one PiZZ, 18 PiSZ, and 61 control subjects (PiMM) underwent complete PFTs, measurement of resistance and reactance in the respiratory system by impulse oscillometry (IOS)/forced oscillation technique (FOT), and CT densitometry. The results were related to self-reported smoking habits. Results: The total lung capacity (TLC) % of the predicted value was significantly higher in the PiZZ ever-smokers than in the PiZZ never-smokers (P

H Laura Aaltonen,1,2,* Simon S Kindvall,3,* Jonas K Jakobsson,4 Jakob Löndahl,4 Lars E Olsson,3,5 Sandra Diaz,1,2 Sophia Zackrisson,1,2 Per Wollmer1,2 1Department of Medical Imaging and Physiology, Skåne University Hospital, Malmö, Sweden; 2Department of Translational Medicine, Lund University, Malmö, Sweden; 3Department of Medical Radiation Physics, Lund University, Malmö, Sweden; 4Department of Design Sciences, Lund University, Lund, Sweden; 5Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital, Malmö, Sweden *These authors contributed equally to this work Background: Airspace Dimension Assessment with inhaled nanoparticles is a novel method to determine distal airway morphology. This is the first empirical study using Airspace Dimension Assessment with nanoparticles (AiDA) to estimate distal airspace radius. The technology is relatively simple and potentially accessible in clinical outpatient settings. Method: Nineteen never-smoking volunteers performed nanoparticle inhalation tests at multiple breath-hold times, and the difference in nanoparticle concentration of inhaled and exhaled gas was measured. An exponential decay curve was fitted to the concentration of recovered nanoparticles, and airspace dimensions were assessed from the half-life of the decay. Pulmonary tissue density was measured using magnetic resonance imaging (MRI). Results: The distal airspace radius measured by AiDA correlated with lung tissue density as measured by MRI (ρ = -0.584; p = 0.0086). The linear intercept of the logarithm of the exponential decay curve correlated with forced expiratory volume in one second (FEV1) (ρ = 0.549; p = 0.0149). Conclusion: The AiDA method shows potential to be developed into a tool to assess conditions involving changes in distal airways, eg, emphysema. The intercept may reflect airway properties; this finding should be further investigated. Keywords: nanoparticles, respiratory diagnostics, distal airspaces, airspace dimension assessment with nanoparticles, magnetic resonance densitometry

Jakob Löndahl,1,2 Jonas KF Jakobsson,1,2 David M Broday,3 H Laura Aaltonen,4 Per Wollmer4 1Division of Ergonomics and Aerosol Technology (EAT), Department of Design Sciences, 2NanoLund, Lund University, Lund, Sweden; 3Faculty of Civil and Environmental Engineering, Technion, Haifa, Israel; 4Department of Translational Medicine, Lund University, Malmö, Sweden Abstract: There is a need for efficient techniques to assess abnormalities in the peripheral regions of the lungs, for example, for diagnosis of pulmonary emphysema. Considerable scientific efforts have been directed toward measuring lung morphology by studying recovery of inhaled micron-sized aerosol particles (0.4–1.5 µm). In contrast, it is suggested that the recovery of inhaled airborne nanoparticles may be more useful for diagnosis. The objective of this work is to provide a theoretical background for the use of nanoparticles in measuring lung morphology and to assess their applicability based on a review of the literature. Using nanoparticles for studying distal airspace dimensions is shown to have several advantages over other aerosol-based methods. 1) Nanoparticles deposit almost exclusively by diffusion, which allows a simpler breathing maneuver with minor artifacts from particle losses in the oropharyngeal and upper airways. 2) A higher breathing flow rate can be utilized, making it possible to rapidly inhale from residual volume to total lung capacity (TLC), thereby eliminating the need to determine the TLC before measurement. 3) Recent studies indicate better penetration of nanoparticles than micron-sized particles into poorly ventilated and diseased regions of the lungs; thus, a stronger signal from the abnormal parts is expected. 4) Changes in airspace dimensions have a larger impact on the recovery of nanoparticles. Compared to current diagnostic techniques with high specificity for morphometric changes of the lungs, computed tomography and magnetic resonance imaging with hyperpolarized gases, an aerosol-based method is likely to be less time consuming, considerably cheaper, simpler to use, and easier to interpret (providing a single value rather than an image that has to be analyzed). Compared to diagnosis by carbon monoxide (DL,CO), the uptake of nanoparticles in the lung is not affected by blood flow, hemoglobin concentration or alterations of the alveolar membranes, but relies only on lung morphology. Keywords: nanoaerosols, lung particle interaction, emphysema, respiratory diagnosis, AiDA, COPD

Kjell Torén,1 Anna-Carin Olin,1 Anne Lindberg,2 Jenny Vikgren,3 Linus Schiöler,1 John Brandberg,3 Åse Johnsson,3 Gunnar Engström,4 H Lennart Persson,5 Magnus Sköld,6 Jan Hedner,7 Eva Lindberg,8 Andrei Malinovschi,8 Eeva Piitulainen,9 Per Wollmer,9 Annika Rosengren,10 Christer Janson,8 Anders Blomberg,2 Göran Bergström10 1Section of Occupational and Environmental Medicine, Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, 2Department of Public Health and Clinical Medicine, Division of Medicine/Respiratory Medicine, Umeå University, Umeå, 3Department of Radiology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, 4Department of Clinical Science, Malmö, Lund University, Lund, 5Department of Respiratory Medicine and Department of Medicine and Health Sciences, Linköping University, Linköping, 6Respiratory Medicine Unit, Department of Medicine Solna, Center for Molecular Medicine, Karolinska Institutet, Stockholm, 7Department of Internal Medicine/Lung Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, 8Department of Medical Sciences, Clinical Physiology and Respiratory, Allergy and Sleep Research, Uppsala University, Uppsala, 9Department of Translational Medicine, Lund University, Malmö, 10Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden Background: Spirometric diagnosis of chronic obstructive pulmonary disease (COPD) is based on the ratio of forced expiratory volume in 1 second (FEV1)/vital capacity (VC), either as a fixed value

Abstract Background Changes in maximum standardised uptake values (SUVmax) between serial PET/CT studies are used to determine disease progression or regression in oncologic patients. To measure these changes manually can be time consuming in a clinical routine. A semi-automatic method for calculation of SUVmax in serial PET/CT studies was developed and compared to a conventional manual method. The semi-automatic method first aligns the serial PET/CT studies based on the CT images. Thereafter, the reader selects an abnormal lesion in one of the PET studies. After this manual step, the program automatically detects the corresponding lesion in the other PET study, segments the two lesions and calculates the SUVmax in both studies as well as the difference between the SUVmax values. The results of the semi-automatic analysis were compared to that of a manual SUVmax analysis using a Philips PET/CT workstation. Three readers did the SUVmax readings in both methods. Sixteen patients with lung cancer or lymphoma who had undergone two PET/CT studies were included. There were a total of 26 lesions. Results Linear regression analysis of changes in SUVmax show that intercepts and slopes are close to the line of identity for all readers (reader 1: intercept = 1.02, R2 = 0.96; reader 2: intercept = 0.97, R2 = 0.98; reader 3: intercept = 0.99, R2 = 0.98). Manual and semi-automatic method agreed in all cases whether SUVmax had increased or decreased between the serial studies. The average time to measure SUVmax changes in two serial PET/CT examinations was four to five times longer for the manual method compared to the semi-automatic method for all readers (reader 1: 53.7 vs. 10.5 s; reader 2: 27.3 vs. 6.9 s; reader 3: 47.5 vs. 9.5 s; p < 0.001 for all). Conclusions Good agreement was shown in assessment of SUVmax changes between manual and semi-automatic method. The semi-automatic analysis was four to five times faster to perform than the manual analysis. These findings show the feasibility of using semi-automatic methods for calculation of SUVmax in clinical routine and encourage further development of programs using this type of methods.

Randomized controlled trials (RCTs) have shown an antidepressant effect of glabellar botulinum toxin (BoNT) injections. In the FDA Adverse Event Reporting System (FAERS) database, BoNT injection is associated with reduced incidence rates of depression across various non-psychiatric indications, which confirms the previous findings independently of specific expectations to an antidepressant effect of BoNT. The rationale of using BoNT to treat depression is to interrupt proprioceptive body feedback that may reinforce negative emotions. Negative emotions also occur in other mental disorders, suggesting a transdiagnostic therapeutic potential of BoNT in psychiatry. Here we report an analysis of the FAERS database, in which we found that, compared to alternative treatments, BoNT injections were associated with lower incidence of anxiety symptoms and related disorders. Among seven indications/injection sites, we found this protective effect of BoNT in cosmetic use/facial muscles, migraine/facial and head muscles, spasms and spasticity/upper and lower limbs, torticollis and neck pain/neck muscles, and sialorrhea/parotid and submandibular glands (reporting odds ratios 0.79-0.27). These findings are encouraging for possible future RCTs on the use of BoNT as a treatment for anxiety and related disorders.

The World Health Organization estimates the number of people suffering from depression to be over 264 million. Current monoamine transmission modulating therapeutics, even with proper adherence and acceptable tolerability, are not effective for nearly one third of the patients, leading clinicians to explore other therapeutic options such as electroconvulsive therapy, transcranial magnetic stimulation, ketamine infusions, and, more recently, glabellar botulinum toxin, BoNT, injections. The scale and mechanism of antidepressant action of BoNT is unclear and maybe hypothetically attributed to the disruption of proprioceptive facial feedback reinforcing negative emotions. Here we verify the antidepressant effect of botulinum toxin by analysis of over 40 thousand BoNT treatment reports out of thirteen million postmarketing safety reports in the FDA Adverse Event Reporting System, FAERS. The results of the analysis indicate that patients who received BoNT injections to treat hyperhidrosis, facial wrinkles, migraine prophylaxis, spasticity, and spasms, had a significantly lower number of depression reports when compared to patients undergoing different treatments for the same conditions. These findings suggest that the antidepressant effect of BoNT is significant, and, surprisingly, is observed for a broad range of injection sites.

Purpose: A variety of fixed-dose combination products is used in the therapy of Parkinson Disease. However, to date a proper analytical method applicable for comparative screening of different antiparkinson products was not available. The objective of the present work was thus to develop and validate an analytical method for the simultaneous quantification of levodopa, carbidopa, benserazide and entacapone. The method should be applicable for quantifying samples from drug release experiments with marketed products and prototype formulations performed under compendial and biorelevant test conditions. Methods: A fast and robust method applicable for separation and quantification of the four compounds was developed and validated according to International Conference on Harmonization guidelines. Method validation covered applicability to a wide concentration range of all compounds and peak separation in complex sample matrices such as biorelevant dissolution media. Results: The compounds were successfully separated by using a gradient elution method on an endcapped LiChrospher 100 RP-18 (250 x 4.6 mm, 5 µm) column coupled with a LiChrospher 100 RP-18 precolumn (4 x 4 mm, 5 µm) at a column temperature of 35.0 °C and a flow rate of 1.50 mL/min. The injection volume was 30 µL and the detection wavelengths were 280 and 210 nm, respectively. For all drug/media combinations the method was linear (r2 > 0.999) for a concentration range corresponding to 1.25 - 125 % label claim (i.e. 200 mg levodopa/entacapone and 50 mg carbidopa/benserazide) released. All other validation parameters were in the specified limits over the same concentration range. Conclusion: The new method allows for robust and fast separation of levodopa, carbidopa, benserazide and entacapone without any interference caused by excipients or ingredients of compendial and biorelevant dissolution media and thus presents a valuable tool in both formulation development and in vitro drug release screening of numerous fixed-dose combinations of antiparkinson drugs. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.